Chewing gum compositions comprising cannabinoids

ABSTRACT

The present invention relates to a chewing gum composition comprising 0.01 to 15% by weight a cannabinoid or a derivative thereof, based on the total weight of the chewing gum composition, and to chewing gums and blistering packages comprising said chewing gums.

FIELD OF THE INVENTION

The present invention relates to a chewing gum composition comprising acannabinoid or a derivative thereof and the use of said chewing gumcomposition for the treatment or alleviation of pain.

BACKGROUND OF THE INVENTION

Cannabis has long been used for medicinal purposes and as a recreationaldrug. The medicinal application is essentially anti-emetic, i.e. thatthe active components of cannabis, i.e. cannabinoids, are effective as adrug against nausea and vomiting which are commonly side-effects ofopioid analgesics, anaesthetics, highly active anti-retroviral therapy(HAART for HIV—AIDS) and chemotherapy for cancer. Cannabis has also beenused for a long period of time as a drug for relieving (chronicneurogenic/neuropathic) pain that is caused by several disorders andsurgical operations. Other medical indications include depression,migraine, multiple sclerosis, fibromyalgia, syndromes like Parkinson andGilles de la Tourette and its use as analgesic, spasmolytic, appetitestimulating, palliative and anti-convulsant medication.

The main constituent of cannabis is delta-9-tetrahydrocannabinol (THC)or dronabinol. Its IUPAC nomenclature is(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol).THC binds to the cannabinoid receptor CB₁ (agonist) which is located inbrain tissue. Other active components of cannabis include cannabidiol(CBD;2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol)and cannabichromene (CBC). CBD is not binding to the CB₁ or the CB₂receptor whereas CBC is believed to have an anti-inflammatory action andwould contribute to the pain relieving effect of cannabis.

Cannabis is usually inhaled by the patient (cannabis is often mixed withtobacco for smoking purposes). Smoking has a rapid onset (minutes) andthe dosage can be easily controlled by the patient. However, smoking isnot always convenient, since it is reported to have an adverse affect onthe respiratory system and many patients just dislike smoking.Additionally, smoking of cannabis includes burning of the herb which maylead to the formation of harmful side-products like noxious carbonmonoxide. Furthermore, the harmful effects of nicotine and tar are wellknown. Although effective, smoking cannabis has many disadvantages.

Another method frequently employed is vaporisation wherein the herb isheated to about 180° C. rather than burned so that harmful side-productsare hardly formed. Additionally, the vapour may be cooled or furtherpurified if desired before inhalation. Furthermore, the dosage is easilycontrolled by the patient since inhalation provides for a rapid onsetand a fast delivery into the bloodstream. However, the use of avaporiser is also not always convenient since it requires a place orspot where the patient can set up and use his or her vaporiser toundergo treatment. In this respect it is also time-consuming.

Oral compositions comprising synthetic THC, e.g. gelatine capsules andtablets, are also known in the art. Marinol® (active component isdronabinol or(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol)is a soft gelatine capsule à 2.5 mg comprising synthetic THC. Adisadvantage of this product is the high price and that it takes aboutan hour to take full effect and the frequent dosage problems encounteredby patients. The bio-availability after oral intake is onlyapproximately 15%. Namisol® (active component is dronabinol) is asublingual tablet à 1.4 mg THC (ultra pure extract from cannabissativa), which is claimed to have a rapid uptake through the sublingualmucosa. The problem is that the tablet has to be kept under the tonguefor the time it takes to dissolve in the saliva.

Cesamet® (active component is nabilone) is a capsule comprising thesynthetic cannabinoid nabilone (racemic(6aR,10aR)-1-hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-7,8,10,10a-tetrahydro-6H-benzo[c]chromen-9(6aH)-one).It is said to have fewer undesired side effects than THC.

Sativex® comprises THC and CBD and is commercially available as a buccalmouth spray for multiple sclerosis and for the alleviation of pain. Eachspray of Sativex® delivers a fixed dose of 2.7 mg THC and 2.5 mg CBD. Itis reported to cause irritation of the oral mucosa (20-25% of thepatients) and to have a bad taste because of the high ethanol content.

However, gelatine capsules comprising THC or similar components appearto be less effective than smoking cannabis or vaporising cannabis andinhaling the vapour formed. Moreover, patients suffering from severenausea due to chemotherapy complained that these oral formulations weredifficult to swallow.

GB 2377633 of GW Pharmaceuticals, incorporated by reference, disclosespharmaceutical compositions comprising cannabinoids having specificratios of cannabidiol (CBD) to tetrahydrocannabinol (THC). Thecompositions are clinically useful in the treatment or management ofspecific diseases or medical conditions.

GB 2381194 of GW Pharmaceuticals, incorporated by reference, disclosespharmaceutical formulations for use in the administration ofmedicaments, in particular lipophilic medicaments, via mucosal surfaces.Example 9 discloses a formulation for buccal use and sublingual tablets.

GB 2414933 of GW Pharma Ltd., incorporated by reference, discloses theuse of a combination of cannabinoids for the treatment of pain,inflammation and/or disease modification in arthritis. The cannabinoidsare selected from CBD or cannabidivarin (CBDV) and THC ortetrahydrocannabinovarin (THCV) and are in a predefined ratio by weightof less than or equal to 19:1 of CBD or CBDV to THC or THCV.

GB 2432312 of GW Pharma Ltd., incorporated by reference, discloses theuse of a combination of cannabinoids in the treatment of neuropathicpain, in particular peripheral neuropathic pain. A combination of CBDand THC may be used, wherein the ratio of CBD:THC by weight is between10:1 and 1:10.

There is still a need in the art for a composition comprising acannabinoid that can be used by a mammal, preferably a human, sufferingfrom pain for the treatment or alleviation of said pain, wherein saidcomposition can be used in a mammal friendly, preferably man-friendly,and socially accepted manner including situations and locations wheresmoking is legally not allowed or is not convenient or is hampering orirritating other mammals, preferably humans, such as in restaurants,train stations, café's and the like. There is further a need in the artfor a composition comprising a cannabinoid or a derivative thereof thatcan be used as a unit dosage form, in particular a unit dosage form thatis easily and safely packed in a suitable carrier, e.g. a blisterpackage so that it can be easily carried by the consumer. There is alsoa need in the art for compositions comprising a cannabinoid or aderivative thereof that allows for controlled release of the cannabinoidor the derivative thereof. Additionally, there is a need in the art forbetter dissolving of lipophilic cannabinoids and improving or maskingthe unpleasant taste of these lipophilic cannabinoids.

SUMMARY OF THE INVENTION

The present invention relates to a chewing gum composition comprising acannabinoid or a derivative thereof. The present invention furtherrelates to the use of said chewing gum composition for the treatment oralleviation of pain.

DETAILED DESCRIPTION OF THE INVENTION

The verb “to comprise” as is used in this description and in the claimsand its conjugations are used in its non-limiting sense to mean thatitems following the word are included, but items not specificallymentioned are not excluded. In addition, reference to an element by theindefinite article “a” or “an” does not exclude the possibility thatmore than one of the elements are present, unless the context clearlyrequires that there is one and only one of the elements. The indefinitearticle “a” or “an” thus usually means “at least one”. Additionally, thewords “a” and “an” when used in the present document in concert with theword comprising or containing denote “one or more.”

The present invention relates in particular to a chewing gum compositioncomprising a cannabinoid or a derivative thereof that allows forcontrolled release of the cannabinoid or the derivative thereof therebyproviding a sustained and prolonged release of the cannabinoid or thederivative thereof, so that a mammal, preferably a human, consuming thechewing gum composition is free of pain or is alleviated from pain for aprolonged period of time.

According to the present invention, it is preferred that the chewing gumcomposition comprises 0.01 to 15% by weight of the cannabinoid or thederivative thereof, more preferably 0.01 to 1.0 wt. %, even morepreferably 0.05 to 0.125% by weight, yet even more preferably 0.1 to0.10% by weight, based on the total weight of the composition.

The chewing gum composition comprising the cannabinoid or the derivativethereof further comprises a gum base as is commonly used in chewing gumformulations that are commercially available and accepted by theconsumer.

The cannabinoid or the derivative thereof may be comprised by a solidmaterial composed of a cellulose which comprises a well-defined amountof the cannabinoid or the derivative thereof, e.g. in and/or onto voidsor pores within the solid material.

Preferably, the chewing gum composition according to the presentinvention has a high initial release rate of the cannabinoid or thederivative thereof to provide a rapid alleviation of pain. Accordingly,it is preferred that the chewing gum composition according to thepresent invention releases at least 1% by weight to not more than 30% byweight, based on the total weight content of the cannabinoid or thederivative thereof in the chewing gum composition according to thepresent invention within five minutes after ingestion. It is alsopreferred that the onset of the release starts within three minutesafter ingestion.

Preferably, the chewing gum composition is non-disintegrating, i.e. itdoes not disintegrate during chewing, and it does not crumble. It iscurrently contemplated that use of a particular gum base in combinationwith a suitable selection of additives has a significant impact on thenon-disintegrating properties of chewing gum compositions. Examples ofsuitable gum bases having suitable properties and leading tonon-disintegrating chewing gum compositions are e.g. gum bases that areor comprise, Gum powder PG 11 TA, Gum powder PG 11 TA New, Gum powder PG5 TA, Gum powder PG 5 TA New and Gum powder PG N12 TA.

The gum base is normally present in the chewing gum compositionaccording to the present invention in an amount of about 25 to about 85%by weight, preferably about 30 to about 80% by weight, more preferablyabout 40% to about 80% by weight and in particular about 50 to about 80%w/w, based on the total weight of the chewing gum composition.

In preferred embodiments of the chewing gum compositions according tothe present invention, the chewing gum composition comprises one or morefurther ingredients, e.g. fats, waxes, emulsifiers, plasticizers, oils,flavouring agents and the like.

The chewing gum composition according to the present invention maycomprise a carrier comprising internal voids. Such voids may at leastpartially comprise said cannabinoid or derivative thereof. The carrieris preferably essentially insoluble in water or has a very lowsolubility in water. Thus, it has typically a solubility in water atroom temperature (25° C.) of less than 1% w/w. Obviously, the solubilityunder intra-oral mouth temperature conditions (which is higher than 25°C.) should also be not too high.

Suitable carriers are certain cellulose, such as a microcrystallinecellulose derivatives, e.g. microcrystalline cellulose or carbohydratesincluding a cellulose derivative, e.g. hemicellulose. The cellulosederivative may be of natural origin, e.g. dextran, agarose, agar,pectin, alginate, xanthan, chitosan, starch. The cellulose derivativemay also be of synthetic or semi-synthetic origin.

A particular suitable material having internal voids is amicrocrystalline cellulose. Specific examples of a suitablemicrocrystalline cellulose is microcrystalline cellulose selected fromthe group consisting of AVICEL(R) grades PH-100, PH-102, PH-103, PH-105,PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL(R) grades 101, 102, 12,20 and EMOCEL(R) grades 5OM and 9OM, and the like, and mixtures thereof.

The chewing gum composition according to the present inventionpreferably further comprises a component selected from the group offlavouring agents, sweetening agents, buffering agents, antioxidants,pharmaceutically acceptable excipients and mixtures thereof.

In order to improve the organoleptic properties of the chewing gumcomposition according to the present invention, the chewing gumcomposition preferably comprises a flavouring agent, e.g., mentholflavour, eucalyptus, mint flavour and/or L-menthol, in an amount ofabout 0.5 to about 12% by weight, more preferably about 1 to about 10%by weight, even more preferably about 1.5 to about 9% by weight, yeteven more preferably about 2 to about 8% by weight, based on the totalweight of the chewing gum composition.

In order to increase the gustatory properties of the chewing gumcomposition according to the present invention, the chewing gumcomposition preferably comprises a pharmaceutically acceptablesweetener, e.g. sugar alcohols including xylitol, sorbitol and/orisomalt, artificial sweeteners such as e.g. aspartame, sucralose,acesulfame potassium or saccharin. The amount of the pharmaceuticallyacceptable sweetener is normally preferably at least about 0.05% byweight, more preferably about 0.075 to about 5% by weight, even morepreferably about 5 to about 35% by weight, yet even more preferablyabout 10 to about 35% by weight, even yet more preferably about 15 toabout 35% by weight and in particular about 20 to about 30% by weight,based on the total weight of the chewing gum composition. It is highlypreferred that the pharmaceutically acceptable sweetener isnon-cariogenic as well as non-carcinogenic.

The chewing gum composition according to the present inventionpreferably comprises a buffering agent. Suitable buffering agents aretypically those selected from the group consisting of acetates,glycinates, phosphates, glycerophosphates, citrates such as citrates ofalkaline metals, carbonates, hydrogen carbonates, and borates, andmixtures thereof. The chewing gum composition preferably comprises abuffering agent in an amount of about 0.5 to about 5% by weight, morepreferably about 0.75% to about 4% by weight, even more preferably about0.75 to about 3% by weight, yet even more preferably about 1 to about 2%by weight, based on the total weight of the chewing gum composition.

The chewing gum composition according to the present inventionpreferably further comprises an anti-oxidant, e.g., ascorbyl palmitateand sodium ascorbate, in an amount of about 0.05 to about 0.3% byweight, more preferably about 0.1 to about 0.25% by weight, yet evenmore preferably about 0.15 to about 0.2% by weight, based on the totalweight of the chewing gum composition.

The pharmaceutically acceptable excipients used in the chewingcomposition according to the present invention are preferably selectedfrom the group of excipients normally used within the pharmaceuticalindustry for the preparation of tablets, i.e. excipients like fillers,desintegrants, binders, lubricants and the like.

Suitable fillers include celluloses and cellulose derivatives includingmicrocrystalline cellulose, hydroxypropylcellulose and sodiumcarboxymethylcellulose, lactose, starches including potato starch andmaize starch (in the US known as corn starch).

Suitable lubricants include stearates including magnesium stearate, talcand colloidal silica dioxide.

Chewing gums can be made from the chewing composition according to thepresent invention by conventional methods.

The chewing gum prepared from the chewing gum composition according tothe present invention may be coated or uncoated.

The chewing gum prepared from the chewing gum composition according tothe present invention may comprise a core coated with one or morelayers, wherein the core and/or one or more layers comprise (a part of)the total content of the cannabinoid or the derivative thereof which ispresent in the chewing gum composition thereby enabling a controlledrelease profile.

The present invention also relates to a blister package comprising achewing gum composition according to the present invention.

The chewing gum composition according to the present invention is usedfor the treatment or alleviation of pain, in particular pain resultingfrom oral and cranio-maxillofacial surgery and/or disorders and/orchronic pain. However, the chewing gum composition according to thepresent invention may also be used to treat or prevent conditionsassociated with or caused by chemotherapy and radiotherapy, includingnausea, vomiting and muscle spasms.

EXAMPLES Example 1 Chewing Gum Preparation

A chewing gum base was used to prepare a chewing gum with containing10.0 mg of THC. Percentages are in percent by weight.

Gumbase: 75.5%  A Xylitol: 13.6%  A Glycerin:  4.5% A Saccharine: 0.38% B H2O: 2.26%: B Peppermint Aroma oil: 1.51%: C Peppermint powder: 1.51%:A THC: 0.69%: C Total: 100% 

-   -   Phase A: The gum base was heated till 90° C. and Xylitol,        glycerin and peppermint powder were added and the whole was        stirred till a homogeneous mass of gum    -   Phase B: Saccharine was dissolved in H₂O.    -   Phase C: The peppermint oil was heated till 60-70° C. and the        THC was added out of a heated syringe and dissolved in the        peppermint aroma oil.    -   Phase B was added to Phase A and stirred vigorously, directly        here after Phase C was added and the whole was stirred        vigorously for approx 7 minutes.    -   The gum base was poured on a plate and cooled down.    -   Hereafter chewing gums with a mass of about 1.5 g were prepared.

Example 2 Case Studies

A chewing gum was chewed for a time period of 20 minutes and arelaxation of the healthy volunteers was observed.

ABBREVIATIONS CBN: Cannabinol CBD: Cannabidiol

THCC3: Tetrahydrocannabivarin or tetrahydrocannabinol-C3

THCC4: Tetrahydrocannabinol-C4 DHC: Dihydrocannabinol THC:Tetrahydrocannabinol CBC: Cannabichromene Method:

Samples were prepared by putting one gum in a 10.0 ml glass laboratorytube. 5.00 ml ethanol was added and the tube was shaken 3 times with a 5minute interval. Then 5.00 ml mobile phase (acetonitrile: H₂O+0.1%formic acid) was added. The tube was shaken and the gum was mashed witha Pasteur pipette. Then the solution was shaken again and the sample wasfiltered through a 0.2 micrometer filter. This is the impurity solution.An assay solution was prepared by diluting the impurity solution 100times with mobile phase. The calculated amount of THC is based uponcomparison with a reference solution with an exactly known amount ofTHC. Purities are calculated as peak area/sum of area's*100%. Impuritiespresent in the placebo are not considered and known impurities arecorrected with known response factors.

Results

TABLE 1 Absolute amounts in three separately measured chewing gums CBN(mg) DHC (mg) THC (mg) CBC (mg) Weight (mg) Canchew 0.01 0.02 2.19 0.011529.3 m1 Canchew 0.01 0.02 2.12 0.01 1593.0 m2 Canchew 0.01 0.02 1.960.01 1515.9 m3

TABLE 2 Purity based on total area CBD THCC3 THCC4 CBN DHC THC CBC SUMTHC 0.32 0.16 0.14 0.27 0.57 98.18 0.36 100 Canchew 0.00 0.00 0.00 0.360.97 98.04 0.62 100 m1 Canchew 0.00 0.00 0.00 0.32 1.04 97.99 0.65 100m2 Canchew 0.00 0.00 0.00 0.40 1.17 97.71 0.73 100 m3

CONCLUSIONS

During the preparation of the chewing gum only a slight degradation ofTHC occurs. The main breakdown product is dihydrocannabinol which is anintermediate to cannabinol.

Extraction of THC from the chewing gum is not very efficient with theused method. The measurements show only 2 mg THC in each tablet. This ishowever not consistent with the added amount of THC. Various minorimpurities in the used THC cannot be measured in the gum, this isbecause these are also ineffectively extracted and therefore in very lowconcentration in the sample.

None of the known breakdown products of THC can be measured andtherefore it is not logical that the THC actually got broken down. Forthis reasons it should be assumed that the individual gums contain about10 mg THC a piece. During some tests it was experienced that the matrixwhich contains the THC is insoluble in most solvents. This makes a goodrecovery and precise measurement extremely difficult. Pentane dissolvedthe gum and is known to be a good solvent for cannabinoids. It istherefore recommended to do extractions with an aliphatic hydrocarbon.Down side to this procedure is that these samples cannot be directlyinjected into a reverse phase HPLC system. Gas chromatography would be agood alternative.

1. A chewing gum composition comprising a cannabinoid or a derivativethereof.
 2. The chewing gum composition according to claim 1, whereinthe chewing composition comprises 0.01 to 15% by weight a cannabinoid ora derivative thereof, based on the total weight of the chewing gumcomposition.
 3. The chewing gum composition according to claim 1, saidcomposition comprising a gum base.
 4. The chewing gum compositionaccording to claim 1, wherein the chewing gum composition comprises aflavouring agent.
 5. The chewing gum composition according to claim 1,wherein the chewing gum composition comprises a pharmaceuticallyacceptable sweetening agent.
 6. The chewing gum composition according toclaim 1, wherein the chewing gum composition comprises a bufferingagent.
 7. The chewing gum composition according to claim 1, wherein thechewing gum composition comprises an antioxidant.
 8. The chewing gumcomposition according to claim 1, wherein the chewing gum compositioncomprises a pharmaceutically acceptable excipient. 9-11. (canceled) 12.A method for treating a mammal in need thereof for the treatment oralleviation of pain, comprising administering to said mammal a chewinggum composition according to claim
 1. 13. The method according to claim12, wherein the pain results from oral and cranio-maxillofacial surgeryand/or disorders.
 14. The method according to claim 12, wherein the painis chronic.
 15. A blister package comprising a chewing gum compositionaccording to claim 1.